ABSTRACT Chronic high frequency electrical stimulation of the brain, called deep brain stimulation (DBS), has evolved from a highly experimental technique to a well-established therapy for the treatment of movement disorders including dystonia, essential tremor (ET), and Parkinson's disease (PD). While the clinical benefits of DBS are well documented, fundamental questions remain about the mechanisms of action. This lack of understanding will limit full development and optimization of this promising treatment. We propose to quantify the effects of temporally non-regular patterns of DBS (i.e., non-constant interpulse intervals) on neuronal activity and motor function across the spectrum of computational models, in vivo animal experiments, and persons with PD or ET. We will first confirm the hypothesis that the symptom reduction from DBS is dependent on the pattern of stimulation, rather than just the rate of stimulation. We expect that symptom relief by DBS will decrease as the stimulus train is made more irregular. Subsequently, we will we will quantify the effects of pauses, bursts, and irregularity in the stimulus train to probe the mechanisms for the ineffectiveness of irregular stimulation. Specific non-regular patterns of stimulation will enable testing of three hypotheses that explain why non-regular stimulation is less effective than regular stimulation. Finally, we will use model-based optimization to design, and subsequently test in animals and humans, novel non-regular stimulation patterns. These patterns are intended to produce symptom relief at a lower average frequency, and thereby reduce the intensity of side effects and increase stimulator battery life. The outcome of the proposed project will address the fundamental question of the effect of the temporal pattern of DBS on relief of motor symptoms and neuronal activity and thus improve greatly our understanding of mechanisms of action. This understanding will inform identification of more easily accessible anatomical locations to deliver DBS and establish a foundation upon which to build future applications of electrical stimulation in the brain.